B cells are one of the targets of Friend virus (FV) infection, a well-established mouse model often used to study retroviral infections in vivo. Although B cells may be effective in stimulating cytotoxic T lymphocyte responses, studies involving their role in FV infection have mainly focused on neutralizing antibody production. Here we show that polyclonal activation of B cells promotes their infection with FV both in vitro and in vivo. Furthermore, we demonstrate that complement opsonization of Friend murine leukemia virus (F-MuLV) enhances infection of B cells, which correlates with increased potency of B cells to activate FV-specific CD8(+) T cells. We also showed that C opsonization of retroviral particles enhances the ability of dendritic cells (DCs) to induce CTL responses both in vitro and in vivo. DCs exposed to C-opsonized HIV in vitro were able to stimulate CTLs to elicit antiviral activity significantly better than non-opsonized HIV. Furthermore, experiments using the Friend virus (FV) mouse model illustrated that the enhancing role of complement on DC-mediated CTL induction also occurred in vivo. Our results indicate that complement serves as natural adjuvant for DC-induced expansion and differentiation of specific CTLs against retroviruses. Although there is extensive evidence that Friend virus (FV)-specific CD8+ T cells from chronically infected mice are dysfunctional, a recent paper by Takamura et al. proposed the new idea, based on marker staining and in vitro assays, that these cells are already dysfunctional during early infection. However, studies in our lab using the same FV stock have produced extensive in vivo and direct ex vivo data demonstrating that FV-specific CD8+ T cells are highly functional and effective during acute FV infections, and that functional exhaustion develops in the initial phase of chronic infection, similar to many other viral infections. For example, mice depleted of CD8+ T cells, compared with nondepleted mice, have greatly increased viral loads. During acute infection, FV-specific CD8+ T cells are highly cytotoxic, as demonstrated by in vivo CTL assays, and when analyzed directly ex vivo, they highly express CD107a, indicating recent cytolytic activity. It appears from the Materials and Methods section that this ex vivo CD107a expression was subtracted as background in the Takamura study. Like Takamura et al., we found that FV-specific CD8+ T cells produce high levels of granzyme B during acute infection, which they surprisingly interpreted as excessive activation rather than evidence of functionality. The preponderance of evidence from numerous studies indicates that the acute FV-specific CD8+ T cell response is not prematurely exhausted but becomes dysfunctional largely as a result of suppression by regulatory T cells.